The helminth parasite Schistosoma mansoni is long lived, causing chronic infections in its natural human and experimental mouse hosts. It is recognized that during schistosomiasis the parasite-induced Th2 response, as measured by in vitro antigen-stimulated T cell proliferation or cytokine secretion assays, peaks early and then declines despite ongoing infection, a process that is referred to as immunomodulation. Immunomodulation in schistosomiasis appears to play a vital role in minimizing immunopathology in a setting where the immune system is incapable of eliminating the pathogen. Here we propose to explore the underlying basis and functional significance of the diminished Th2 responses that characterize chronic schistosomiasis. We hypothesize that chronic schistosome infection leads to a state of Th2 cell dysfunction akin to adaptive tolerance. We propose to test this hypothesis through three specific aims: 1. To use IL-4 reporter mice to characterize Th2 cells throughout infection. 2. To establish whether Th2 cells from chronically infected mice are irreversibly dysfunctional or whether ongoing environmental signals are required to maintain them in this state. 3. To identify the mechanism responsible for immunomodulation during chronic infection. Recently, using 4get and KN2 IL-4 reporter mice, in which IL-4 transcription and protein production are reported by the expression of GFP and surface human CD2 respectively, we have been able to unequivocally identify CD4 T cells that have responded during infection and committed to Th2 differentiation by becoming capable of making IL-4. These cells can be detected immediately ex-vivo, and indeed in situ, and have allowed us to make significant steps forward in understanding what is happening during chronic schistosomiasis. Together, our studies promise to generate new insights into the processes that allow the regulation of Th2 responses during chronic schistosomiasis and are likely to be of relevance to other chronic helminth infections where Th2 cell hyporesponsiveness has been documented. We believe that our work has the potential to identify targets for intervention in important diseases of the developed world, such as asthma, allergy and ulcerative colitis, that are mediated by chronic, poorly controlled Th2 responses. Schistosomiasis is an important chronic tropical disease caused by long-lived parasitic worms. During the chronic stage of infection with this parasite, the immune response is controlled and diminishes through mechanisms that are poorly understood and which will be investigated in details as part of this proposal. We believe that our work has the potential to identify targets for intervention in important diseases of the developed world, such as asthma, allergy and ulcerative colitis, that are mediated by chronic, poorly controlled Th2 responses.